Over a longer period, leptin secretion by adipose tissue (fat deposits) also reduces appetite. A fall in food intake and fasting inhibits these signals, but stimulates secretion of ghrelin from the stomach, leading to increased appetite and the sensation of hunger. Circulating fatty acids, ketone bodies and amino acids augment the effect of glucose. The major action of insulin is to stimulate glucose uptake, with the subsequent manufacture of glycogen and triglycerides by adipose, muscle and liver cells. Insulin release is reduced as the blood glucose concentration falls, and is further inhibited by catecholamines (Chapter 52) acting at -cell 2-adrenoceptors (Chapters 8 and 52). Low blood glucose initiates glucagon release directly and also drives nervous and hormonal release of catecholamines, which activate -adrenoceptors (Chapters 8 and 52) on cells to augment glucagon release. In liver cells, this results in the inhibition of glycogen synthesis and the activation of glycogen breakdown systems. Similar effects are obtained in muscle cells to increase circulating levels of glucose. There are interactions between glucagon and insulin within the islets: insulin inhibits -cell release of glucagon, but glucagon stimulates the release of insulin, an effect that ensures a basal level of insulin release irrespective of glucose levels. Three main types of cell have been identified within the islets: peripherally located (also known as A) cells, which manufacture and secrete glucagon; centrally located (or B) cells for the production and release of insulin; and (or D) cells that synthesize and liberate somatostatin. The exact role of somatostatin has not been established, but it may be involved in controlling the release of the other two hormones. Insulin release is stimulated initially during eating by the parasympathetic nervous system and gut hormones, such as secretin (Chapter 42), but most output is driven by the rise in plasma glucose concentration that occurs after a meal this disease is caused by failure of -cell function, either by autoimmune attack, in which the immune system (Chapter 11) misidentifies the cells as non-self and destroys them, or by pathologies, such as obesity, that impair insulin release. The former type of disease is usually early onset and is treated with insulin (insulin-dependent diabetes), whereas the latter develops later and is treated by diets that lower blood glucose levels or drugs that stimulate insulin release (non­insulin-dependent diabetes). Untreated, the condition leads to chronically high levels of plasma glucose (hyperglycaemia), overloading the kidney glucose transporters so that glucose begins to appear in the urine (Chapter 36). The osmotic effect of glucose leads to excess production of urine (polyuria) that tastes sweet (this used to be the diagnostic test for diabetes, and gives the disease its name; Latin mellitus = sweet). Long-term hyperglycaemia drives excessive lipolysis by liver cells, leading to a build-up of ketone bodies and the condition known as ketoacidosis (Chapter 39). Long-term complications of diabetes include damage to small blood vessels, especially in the retina and renal nephron (diabetic retinopathy and nephropathy). Ventromedial hypothalamus Gonadotrophinreleasing hormone Arcuate nucleus Growth Dopamine hormone- (prolactin releasing inhibitory hormone factor) Paraventricular nucleus Oxytocin Antidiuretic Corticotrophin- Thyrotrophinhormone releasing releasing hormone hormone Periventricular nucleus Somatostatin Melanotrophin- Melanotrophin releasing inhibitory factor factor Anterior pituitary hormones Melanocytestimulating hormone Luteinizing hormone Folliclestimulating hormone Growth hormone Prolactin Adrenocorticotrophic hormone Thyroidstimulating hormone Pigmentation Reproduction Growth Stimulatory Lactation Inhibitory Stress Metabolism Physiology at a Glance, Fourth Edition. The most important hypothalamic areas for endocrine function are the paraventricular, periventricular, supraoptic and arcuate nuclei, and the ventromedial hypothalamus. The anterior pituitary develops from tissues originating in the roof of the mouth, is non-neural and is sometimes known as the adenohypophysis. The posterior gland is really an extension from the hypothalamus itself, consists of neural tissue and is referred to as the neurohypophysis. As befits their developmental origins, the adeno- and neurohypophyses are controlled in different ways. It should be noted that some hypothalamic hormones control more than one pituitary hormone. The signals that drive the release of posterior gland hormones are entirely neural, so that the hormones are said to be involved in neuroendocrine reflexes. These hormones operate over shorter time courses (minutes) than most endocrine events (hours to days). Oxytocin, however, is involved in positive feedback mechanisms (Chapters 55 and 56). Pulsatile release of pituitary hormones Hormones released from the hypothalamus tend to appear in the blood in discrete pulses, rather than as continuous secretions. This is achieved by the synchronous activation of hormonereleasing neurones of the hypothalamus. As will be seen in later chapters, episodic release has profound implications for the operation of the endocrine system. It also raises a number of interesting and as yet unanswered questions as to how many separate and more or less widely scattered neurones can be activated simultaneously to give rise to pulsatile release. The thyroid gland is formed from clusters of cells (follicles) that surround a gel-like matrix or colloid, the primary constituent of which is the glycoprotein thyroglobulin. The thyroid hormones and their intermediates are highly lipophilic and would escape from the gland were they not incorporated into thyroglobulin, which thus acts as a nucleus for the manufacture of the hormones and as a storage site. Free T1 and T2 are deiodinated by enzymatic action before they can leave the cell. The average plasma concentration of T3 is roughly one-sixth of that of T4, and much of that derives from deiodinated T4. Thyroid receptors are present in almost all tissues, with particularly high levels in the liver and low levels in the spleen and testes. Synthesis and release production, for instance when the core temperature falls, lead to enhanced activation of the thyroid axis. The effects take up to 4 days to reach a maximum, a slow time course that is characteristic of hormones acting through nuclear receptors. Other important actions of thyroid hormones include a generalized increase in protein turnover. These actions can be described as generally catabolic (Chapter 46), but it should be noted that low doses of thyroid hormones have an overall anabolic action and that the hormones are essential to normal postnatal growth. In fetal and neonatal life, underproduction of thyroid hormones causes inadequate somatic and neural development and gives rise to cretinism, a condition characterized by subnormal stature and mental ability. In adults, the main symptoms of thyroid insufficiency are lethargy, sluggishness and an intolerance to cold. In severe cases, there is excess production of water-retaining mucoproteins in subcutaneous tissues, giving rise to tissue bloating, known as myxoedema. When the cause of hypothyroidism is an insufficiency of iodide intake, cells of the thyroid gland undergo hypertrophy and the gland becomes enlarged to form a goitre. This (now very uncommon) condition is treated by ensuring an adequate supply of dietary iodide. The last of these symptoms can eventually lead to ventricular arrhythmias and/or heart failure, and so treatment, usually surgical removal of part of the gland or antithyroid drugs, is highly recommended. Disorders of the thyroid gland Physiological roles of thyroid hormones Basal levels of thyroid hormone release are essential to maintain a normal metabolic rate. As they mature, cells develop specializations according to the tissue of which they are a part (differentiation). In tissue development, excess production of cells is the norm, so that the final shaping of organs depends on programmed death (apoptosis) of supernumerary cells. Some tissues, such as nerve and skeletal muscle, reach a stage of terminal differentiation in adulthood and undergo no further cell division. However, most cells in the adult retain the ability to divide, allowing tissues. The processes of mitosis, cell growth and apoptosis are controlled by a large number of systemic and local peptide hormones, known as growth factors (Chapter 45). To varying extents, these factors stimulate mitosis (they are mitogens), promote growth (a trophic effect) and inhibit apoptosis (promote cell survival). Growth factors are classified into a number of families based on common amino acid sequences and the types of receptor that they activate. It stimulates division, growth and survival in a number of cell types, and is important in tissue repair after injury. The products of these genes are transcription factors, driving the expression of further genes, such as those that produce G1 cyclins, proteins that are required for cell division. Cancer cells do not recognize the normal constraints of organ growth or the limits to the number of divisions to which cells are normally subjected, and are unusually mobile. These features make cancer cells extremely dangerous, as they supplant healthy tissues and cause fatal damage to physiological systems. Cancerous growths start with mutations in particular genes (oncogenes) that impact on cell division and/or apoptosis. In view of the importance of this pathway in mitogenesis, it is not difficult to see how the abnormal activation of these genes could lead to excessive cellular proliferation. In this situation, the signals involved in normal tissue growth provide the driving force for tumour growth and survival. The key signals involved in these processes are growth hormone, thyroid hormones (Chapter 48), sex steroids (Chapters 53 and 54) and growth factors (Chapter 49). The release of the hormone increases immediately after birth before subsiding to a low level for most of prepubertal life. There is another surge in release around the time of puberty, after which plasma concentrations again fall and then continue to decline steadily into old age. The release of the hormone varies throughout the day, with the highest levels achieved during deep sleep. To provide energy for growing tissues, growth hormone has an anti-insulin action in increasing plasma glucose and stimulating lipolysis (Chapter 46). However, its overall effect is anabolic, increasing protein synthesis in many tissues. The lifetime release of growth hormone is regulated by the genetic factors that determine body size, but full expression of its effects requires adequate supplies of metabolic fuels and the presence of the other hormones mentioned above. The overproduction of growth hormone in children is associated with gigantism, and underproduction with dwarfism, which is much more common. Dwarfism is currently treated with human growth hormone manufactured by genetically engineered bacteria. Excess growth hormone release in adults leads to disproportionate growth of the bones of the face and limb extremities, a condition known as acromegaly. Cortical or compact bone has a dense structure and provides most of the strength of the skeleton. It forms the outer layer of all bones and is particularly prevalent in the diaphyses (shafts) of limb bones. Trabecular or spongy bone has a more open structure than cortical bone and surrounds the marrow. In development, bones grow from the interface between the epiphysis and the diaphysis (the growth plate). The elongation of bones involves the laying down of new collagen matrix at the growth plate by rapidly dividing chondrocytes, followed by calcification (hydroxyapatite deposition) through the action of osteoblasts. This stage is known as epiphyseal closure, a process driven by the high levels of sex steroids present at puberty. Even in adults, bones remain dynamic structures, with substantial proportions of the skeleton (25% of trabecular bone and 3% of cortical bone) being replaced by new growth every year. Osteoblasts develop into osteocytes, cells with numerous processes that settle into spaces in the bone matrix. Osteocytes maintain the integrity of the matrix, but can also secrete acids that dissolve hydroxyapatite and thus provide free Ca2+ to the circulation when required (Chapter 51). Osteoclasts are large cells similar to macrophages (Chapter 11) that remove old bone matrix so that it can be replaced by new material. The collective activity of these cells allows bone to be remodelled throughout life to cope with changes in skeletal stresses, and plays an essential role in the repair of broken bones. They are composed of an organic matrix made up of the structural protein After the menopause women lose bone mass, leading to a weakening of the skeleton with a consequent increase in the likelihood of fractures in older women. The condition can be successfully treated by the administration of oestrogen (hormone replacement therapy). Recent evidence suggests that bone destruction in rheumatoid arthritis may also be driven by cytokines. Ca2+ ions are triggers in so many crucial events that free intracellular Ca2+ must be maintained at a very low level (Chapter 2). External to cells, Ca2+ ions contribute to the blood clotting cascade (Chapter 10) and the normal functioning of Na+ ion channels (Chapter 4). When extracellular Ca2+ is too low, Na+ channels open spontaneously, leading to involuntary contractions of skeletal muscles, described as hypocalcaemic tetany. It is released from chief cells of the four (or more) parathyroid glands located immediately behind the thyroid gland, when the plasma concentration of Ca2+ decreases. Calcitonin is a 32-amino acid peptide released from C cells of the thyroid gland in response to high levels of plasma Ca2+ ions. Calcitonin inhibits bone resorption by osteocytes and may inhibit reabsorption in the kidney, so reducing plasma levels of the ion. The primary source of supply is the diet, with ergocalciferol derived from plants and yeasts and cholecalciferol from animal (particularly dairy) products. Unusually for a vitamin, cholecalciferol can be manufactured within the body via a reaction that is enabled by ultraviolet irradiation of the skin. The final reaction is the slowest step in the process and therefore regulates the speed of the entire chain of reactions. Its receptors are members of the superfamily of steroid receptors and are located inside target cells. Without the hormone, Ca2+ uptake is severely impaired to the point at which intake of the hormone is insufficient to maintain body stores. A lack of D vitamins in children leads to inadequate calcification of bones, which become malformed. Severe vitamin D deficiency in adults leads to bone wasting, a condition known as osteomalacia, with symptoms similar to those of osteoporosis (Chapter 50). Vitamin D and 1,25-dihydroxycholecalciferol Other hormones affecting calcium Growth-promoting hormones (growth hormone, thyroid hormones and sex steroids) tend to promote the incorporation of calcium into bones (Chapter 50). Excess corticosteroids (Chapter 52) inhibit calcium uptake from the gut and reabsorption from the kidney. The inner core (the adrenal medulla) releases the catecholamine hormones adrenaline (epinephrine) and noradrenaline (norepinephrine). It develops from neuronal tissue and is functionally part of the sympathetic nervous system (Chapter 8). The outer layers of the gland (the adrenal cortex) originate from mesodermal tissue and secrete steroid hormones, primarily under the control of the anterior pituitary gland (Chapter 47).

Additional information:

• Clarithromycin

By way of an example, human bone marrowderived multipotent stem cells have been shown to induce therapeutic neovascularization and cardiomyogenesis in a rat model of myocardial infarction. Knowledge is steadily accumu lating concerning the various growth factors required to guide relatively undifferentiated stem cells into the desired mature form, for example pancreatic, nerve, or liver cells for regenera tive therapy, or erythrocytes for transfusion. An exciting development came a few years back from the cloning of "Dolly" the sheep, the first cloned animal produced from a cell taken from an adult animal. Such reproductive cloning has led to concerns that cloned human embryos could be reimplanted and used in attempts to produce cloned humans. However, in therapeutic cloning the embryo is only allowed to grow for a few days in order to provide a source of stem cells for subsequent differentiation and expansion in vitro. A major step in this direction was the announcement in 2005 that a team at the University of Newcastle in the United Kingdom had succeeded in their attempts to clone a human blastocyst. More recently several groups have been able to genetically reprogram adult tissue cells by introducing genes encoding a number of transcription factors in order to generate what are referred to as induced pluripotent stem cells. Stem cell therapy is also being actively explored for the treatment of heart disease, dia betes, visual impairment, and many other afflictions. Clinical experience in grafting Privileged sites Corneal grafts survive without the need for immunosuppres sion. Grafts of cartilage are successful in the same way but an additional factor is the protection afforded the chondrocytes by the matrix. With bone and artery it does not really matter if the grafts die because they can still provide a framework for host cells to colonize. Patients are already partially immunosuppressed at the time of transplantation because uremia causes a degree of immunological nonresponsiveness. Undifferentiated cells are obtained directly from the patient either as adult stem cells or by cell nuclear replacement into enucleated oocytes. They are cultured in a biodegradable matrix with appropriate growth factors to provide a tissue populated with differentiated cells that can function as an autologous graft. Aside from the rejection problem, it is likely that the number of patients who would benefit from cardiac replacement is much greater than the number dying with adequately healthy hearts. Given this rela tive lack of donors more attention is being given to the possi bility of gene therapy, tissue engineered hearts, xenogeneic grafts, and mechanical substitutes. The hepatotrophic capacity of tac rolimus is an added bonus that makes it the preferred drug for liver transplantation. Rejection crises are dealt with by high dose steroids and, if this proves ineffective, antilymphocyte globulin. The use of a synthetic colloidal hydroxyethyl starch solution containing lactobionate allows livers to be preserved for 24 hours or more and has revolutionized the logistics of liver transplantation. To improve the prognosis of patients with primary hepatic or bile duct malignancies, which were consid ered to be inoperable, transplantation of organ clusters with liver as the central organ has been used. Nonetheless, the outcome is not very favorable in that up to threequarters of the patients transplanted for hepatic cancer have recurrence of their tumor within 1 year. For the future we must look forward to the creation of autologous liver from adult cells when tissue engineering techniques have been devel oped sufficiently. The synergy between cyclosporine and rapa mycin is also exploited to beneficial effect. These drugs are initially given at a relatively high dose, the induction phase, for the first few months following transplantation when the antidonor immune response is at its most vigorous, and then at reduced concentrations for the subsequent maintenance phase that is usually required throughout life. If kidney func tion is poor during a rejection crisis, renal dialysis can be used. When transplantation is performed because of immune complexinduced glomerulonephritis, the immunosuppres sive treatment used may help to prevent a similar lesion developing in the grafted kidney. For kidney the higher figure is for transplants from living donors, the lower value the more common situation of organs from deceased donors. Liver transplants survive for a similar time whether or not they are from living or deceased donors. Many of the animals retained the grafted organs in a healthy state for many months without any form of immunosuppression and enjoyed a state of unresponsiveness to grafts of skin or kidney from the same donor. Work is in progress on the transfer of isolated hepatocytes attached to collagencoated microcarriers injected intraperito neally for the correction of isolated deficiencies such as albumin synthesis. This attractive approach has much wider application as a general vehicle for gene therapy. Current therapy uses steroids such as prednisolone in combination with either cyclosporine or tacrolimus, but inclu sion of methotrexate in this regimen is said to improve efficacy. There is hope that Treg cells can be harnessed to limit this process, and experiments in animal models are in progress to evaluate the efficacy of such approaches. Other organs and tissues It is to be expected that improvement in techniques of control of the rejection process will encourage transplantation in several other areas, for example in type 1 diabetes where the number of transplants recorded is rising rapidly. Transplantation with iso lated islet cells is a more attractive option that avoids the need for major surgery and appears to require less immunosuppres sion than that required following transplantation of a pancreas. Collagenase is injected into the pancreatic duct in a brain dead donor and the recovered islets purified by density gradient cen trifugation. These are then infused into the hepatic portal vein of the recipient, from where they lodge in the liver sinusoids. Recently, the procedure has been successfully extended to using islets isolated from a fragment of pancreas removed from a liv ing donor. The benefits of islet cell transplantation as an alter native to insulin injections do, of course, need to be weighed against the risks of the immunosuppression that is required. One also looks forward to the day when the successful transplantation of skin for lethal burns becomes more commonplace. Some patients were able to discontinue treatment with ldopa for a period of several years. However, 454 / part 2: applied immunology such transplantation is far from routine and the results from clinical trials have been very mixed. As already mentioned, researchers are turning to stem cells as a source of neurons. Induced pluripotent stem cells can be generated from adult patients, avoiding the need for tissue matching and circum venting ethical objections to the use of embryonic stem cells. However much remains to be learnt regarding the mechanisms involved in the cell fate decisions that determine whether these cells develop into neurons, astrocytes, or other cell types. Infertility, including that resulting from medical interven tion such as cytotoxic therapy of cancer patients, is of great concern. It is therefore gratifying to hear of the successful preg nancy outcomes of women who have received ovarian trans plants. More recently several women have been successfully transplanted with a uterus donated by their mothers or a close relative. Cryopreservation of sperm is a successful strategy in the management of adult male cancer sufferers to protect the sperm from mutagenic cancer treatment. This is not available to prepubertal boys, but an alternative for them is cryopreser vation of their spermatogonial stem cells for reintroduction posttreatment, as the Sertoli cells that support differentiation into mature spermatozoa will function normally. There is a potential for identifying and correcting genetic defects in the spermatogonia before their reintroduction, but ethical com mittees fight shy of this sort of "Frankenstein" tinkering. More acceptably, in cases of male infertility due to dysfunctional Sertoli cells, it should be possible to develop mature spermatids by culture of the spermatogonia with Sertoli cells derived from a normal individual. A small number of individuals have received hand or face transplants, but these types of procedures throw up substantial surgical and ethical problems and are still at an early stage of development. Substantially more common, of course, is coronary bypass surgery, which involves autografting with the saphenous vein from the leg, the internal mammary arteries, or the radial artery from the arm. The blood vessel is grafted onto the heart to bypass a blocked or damaged coronary artery. Work proceeds on the generation of engineered blood vessels, for example by using human stem cells grown on biodegradable fibronectincoated polymer scaffolds in the presence of appropriate mediators such as vascular endothelial growth factor. Mice in which the gene for the Crry complement regulatory protein has been knocked out develop placental inflammation and fetal loss. Immunohistochemical analysis revealed a depo sition of complement components in the placenta of these mice, but if they were bred with mice in which complement component C3 has been knocked out then the detrimental effect of the absence of Crry was abrogated. This clearly indi cates a role for inhibition of complement activation as one of the mechanisms that helps maintain the semiallogeneic fetus, at least in mice. The presence of Fasligand at the trophoblast maternal­fetal interface may contribute towards limiting immunological aggression towards the fetus, although the fact that gld mice that lack FasL and lpr mice that lack Fas give birth to live offspring suggests that this mechanism is not essential for the maintenance of pregnancy. The absence of such Tregulatory cells has Graft rejection is an immunological reaction · It shows specificity, the second set response is brisk, it is mediated by lymphocytes and antibodies specific for the graft are formed. It has also been proposed that, at least in mice, chemokine gene silencing in decidual stromal cells limits infiltration by Th1 and Tc1 cells. Mechanisms of graft rejection · Preformed antibodies cause hyperacute rejection within minutes. Dendritic cell precursors can also induce tolerance through antigen presentation in the absence of B7 costimulators. Xenografting · Strategies are being developed to prevent hyperacute rejection of pig grafts in humans due to reaction of natural antibodies in the host with galactose 1,3galactose epitopes on pig cells and acute vascular rejection by acquired antibodies produced by the xenogeneic antibody response. Stem cell therapy · Stem cells can be isolated from various adult tissues and have the potential to provide material for autografts. Clinical experience in grafting · Cornea and cartilage grafts are avascular, produce local immunosuppressive factors, and are comparatively well tolerated. Isolated islets cells from the pancreas are increasingly being used for the treatment of patients with type 1 diabetes. In earlier chapters we have discussed how the immune system becomes activated in response to infectious agents that breach barrier tissues and mounts an appropriate response, via a combination of innate and adaptive components. In the absence of this licensing, productive T and Bcell activation do not take place, thereby minimizing the likelihood of autoimmunity and unwarranted immune responses. If productively activated, Tcells further differentiate to effector cells, coordinating Bcell responses, macrophage activation, and cytotoxic cell killing, in addition to other functions. In this way, the innate and adap tive arms of the immune system work cooperatively to identify and confront microorganisms. The immune system has evolved to discriminate self from nonself based upon the pragmatic principle that anything recognized as nonself may be dangerous and therefore warrants expulsion from the body. In the relent less pursuit of nonself our wellmeaning immune systems sometimes work against us, rejection of transplanted organs being a case in point. But there are also situations where self may give serious cause for concern; cancer being the preeminent example of this. As we shall see, cancer all too frequently results in a situation where our immune systems are presented with a dilemma that, at best, leads to a failure of our immune forces to be immobilized in response to the threat and, at worst, to the immune system becoming recruited in favor of the tumor. To compound matters further, cancers frequently behave similar to wounds, attracting the attentions of the immune system but receiving a helping hand rather than the hostile response that would be more appropriate. This makes good sense as infection is a much more potent selective pressure, from a genetic perspective, than cancer as the latter generally does not prevent us from successful delivery of our genes into the next generation. Understandably, therefore, our immune systems have evolved to be much more focused on infection rather than mutation as a threat to our longterm survival. Thus, although the mutational processes associated with the development of cancer frequently generates neoantigens that, in principle, can elicit Tcell responses, in practice such responses are highly muted because of mechanisms that serve to prevent the emergence of autoimmunity. Moreover, tumors also actively manip ulate the immune system to minimize immune responses that do emerge. Indeed, there is a growing body of evidence that tumors frequently recruit macrophages, neutrophils, as well as other innate immune cells and "reeducate" such cells towards a woundhealing phenotype for the purposes of supporting tumor growth and survival. Another major impediment to the development of robust antitumor immune responses is the fact that tumors arise in a stepwise fashion, over long periods of time, which permits the selection of cells that are effectively invisible to the immune system. If they are not, such cells are weeded out by the immune system as the tumor develops. This process of immunoediting unfortunately selects for the "fittest" tumors that, by definition, are very difficult for the immune system to deal with. Introduction A major problem with cancer is that the immune system has considerable difficulty in mounting robust and/or sustained immune responses against such entities, largely because of the understandable preoccupation of our immune system with recognition of nonself. Because the majority of cancers arise later in life, whereas infectious agents pose a threat from the moment we are born, our immune systems are Cellular transformation and cancer In simple terms, cancer is a state where cells escape the normal controls that govern cell division and cellular longevity among other things. Because our constituent tissues are made up of billions of cells that have long since given up the independence (but also the limitations) that go with being cellular sole traders, there are some hard and fast rules to live by. These rules govern cell division, cell lifespan, cell movement, and cell function. Tight control over cell division is maintained within complex organisms and this ensures that all organs reach a predictable size, which is achieved through regulating the supply of tissuespecific growth factors. In general, growth factors are supplied in a paracrine manner to ensure that cells are dependent on other cells to provide them with the permission to divide. As we shall see, cancers often overcome this restriction through acquiring the ability to make their own growth factors or through mutations that mimic signals provided by growth factors. Thus, a cell born in the skin, stays in the skin, a hepatocyte does not stray from the liver, and a cardio myocyte stays in the heart; differentiated cells do not take vaca tions to other parts of the body. A very important exception to this rule is granted to cells of the immune system, which, by virtue of their role in sniffing out unwelcome guests, are granted permission to enter tissues and nose around looking for things that are out of place. But cells of the immune system are the exception, the vast majority of normal untransformed cells do not move out of their local environment; if they do, they typically die via apoptosis. A third basic rule within multicellular organisms is: live for as long as you are efficiently performing your intended function. Cells that become injured, infected or senescent are typically killed (or kill themselves via apoptosis) and replaced. Although it might seem harsh that cells within our bodies do not have pension plans, Nature knows a thing or two about survival of the fittest, and in the latter game, to fail to make tough choices is to risk losing the whole herd.

CALCIUM HYDROXYAPATITE (Calcium). Imodium.

• High blood pressure.
• Preventing stroke.
• Preventing bone loss caused by insufficient calcium in the diet. This can reduce the risk of breaking bones.
• Preventing colorectal cancer.
• Reducing phosphate levels in people with kidney disease.
• Reducing bone loss in people taking drugs called corticosteroids.
• Use as an antacid as calcium carbonate.
• Are there any interactions with medications?

Source: http://www.rxlist.com/script/main/art.asp?articlekey=96760

Unlike atopic asthmatics, intrinsic asthmatics have negative skin tests to common aeroallergens, no clinical or family history of allergy, normal levels of serum IgE, and no detectable specific IgE antibodies to common allergens. Hayfever the most common manifestations of hayfever, which will be all too familiar to many reading this text, are rhinitis (inflammation inside the nose causing sneezing and the nose to become blocked or runny) and conjunctivitis (redness and inflammation of the conjunctiva of the eyes, which feel itchy). Although not a particularly serious disease, it can have a substantial negative impact on quality of life. Allergic rhinitis shares many pathological features with asthma, which is perhaps not too surprising considering that both conditions affect the airways. However, although there is often extensive damage to the epithelium in asthma, there is usually rather minimal damage to the nasal epithelium. Eczema the barrier function of skin plays a key role in excluding allergens and mutations in the gene encoding filaggrin, a key component of the barrier, are found in some patients with Chapter 14: allergy and other hypersensitivities / 415 atopic dermatitis (eczema). Interleukin31, in particular, has inhibitory effects on the differentiation of epidermal cells. Patients with atopic dermatitis are prone to infection, particularly with Staphylococcus aureus, and as the skin lesions develop there is increasing involvement of Th1, Th17, and Th22 cells in response to microbial challenges. In one study looking at peanut allergy, monozygotic twins had a concordance rate of 64% compared to 7% in dizygotic twins. It is clear that the development of atopic allergy depends upon complex multiple genetic interactions with various environmental factors. Age, sex, infection history, nutritional status, and allergen exposure all play a role. At the time of birth the neonatal immune system is skewed towards Th2type responses, but in the face of a hostile microbial environment there is a shift towards Th1 responses. This shift extends to inhaled allergens, and is sometimes referred to as immune deviation. This idea forms the basis of the hygiene hypothesis put forward to explain the rise in allergies seen in highly developed countries, and even more tellingly in countries that become highly developed, such as the former East Germany, where levels of atopic allergy started to catch up with those in West Germany following reunification. The overall picture relating to economic development is, however, complex ­ let us not forget that a finger has been pointed at environmental pollutants such as diesel exhaust particles as cofactors for asthma attacks. Recently there has also been a great deal of interest in trying to more fully understand the role of the barrier function of the epithelium in allergic responses. Compromise of the normally tight junctions between the epithelial cells, perhaps caused by chemical or physical pollutants or by infection, will clearly lead to increased access of both pathogens and allergens. Diagnosis Sensitivity is normally assessed by the response to intradermal challenge with antigen. The correlation between skin prick test responses and measurement of allergenspecific serum IgE is fairly good. In some instances, intranasal challenge with allergen may provoke a response even when both of these tests are negative, probably as a result of local synthesis of IgE antibodies. Allergen avoidance In individuals where the offending allergen(s) has/have been identified, avoidance of contact with the allergen(s) is desirable but sometimes problematic. Desensitization immunotherapy Repeated subcutaneous injection of small amounts of allergen can lead to worthwhile improvement in individuals subject to insect venom anaphylaxis or hayfever. Studies are ongoing to assess the benefit of extending this approach to (a) 60 Family history (b) 100 IgE levels Percentage children with atopy 80 40 Percentage with atopy None One Both 60 20 40 20 0 0 <0. Multiple genes have been implicated that act at various stages in the type I hypersensitivity response. Events and treatments relating to local anaphylaxis are in green and to chronic inflammation in red. Additionally, Tlymphocyte cooperation is important for IgE synthesis and eosinophilmediated pathogenesis, and therefore the beneficial effects of antigen exposure may also be mediated through induction of anergic or regulatory Tcells and a switch from Th2 to Th1 cytokine production. Thus there are far fewer receptors on the mast cell to bind IgE, and virtually no IgE to be bound anyway. Omalizumab is also licensed for use in adults and adolescents with chronic idiopathic urticaria whose symptoms are not fully controlled by antihistamines. Inhibiting the effector cells Much relief has been obtained with agents such as inhalant isoprenaline and sodium cromoglycate (cromolyn sodium), which prevent mast cell activation. Sodium cromoglycate blocks chloride channel activity and maintains cells in a normal resting physiological state, which probably accounts for its inhibitory effects on a wide range of cellular functions, such as mast cell degranulation, eosinophil and neutrophil chemotaxis and mediator release, and reflex bronchoconstriction. The triggering of macrophages through allergen interaction with surfacebound IgE is clearly a major initiating factor for late reactions, as discussed earlier, and resistance to this stimulus can be very effectively achieved with corticosteroids. Unquestionably, inhaled corticosteroids have revolutionized the treatment of asthma. Their principal action is to suppress the transcription of multiple inflammatory genes, including in the present context those encoding several cytokines. Mediator antagonism Histamine H1receptor antagonists have for long proved helpful in the symptomatic treatment of atopic disease. Newer drugs of this class such as loratadine and fexofenadine are effective in rhinitis and in reducing the itch in atopic dermatitis, although they have little benefit in asthma. Cetirizine additionally has useful effects on eosinophil recruitment in the late phase reaction. Shortacting selective 2agonists such as Ventolin, the active ingredient of which is albuterol (salbutamol), are inhaled to alleviate mildtomoderate symptoms of asthma. An important advance was the introduction of longacting 2agonists such as salmeterol and formoterol which, although potentially carrying a risk of substantial sideeffects, protect against bronchoconstriction for over 12 hours and can be used over a short 418 / part 2: applied immunology period to bring symptoms under control when treatment with other drugs are insufficient. Potent leukotriene receptor antagonists such as montelukast are also effective in asthma and allergic rhinitis. Limiting chronic inflammation Certain drugs impede atopic disease at more than one stage. Cetirizine is a case in point with its dual effects on the histamine receptor and on eosinophil recruitment. Corticosteroids seem to do almost everything; apart from their role in stabilizing macrophages, they solidly inhibit the activation and proliferation of Th2 cells, which are the dominant underlying driving force in chronic asthma, and may call a halt to the development of irreversible narrowing of the airways. Functionally this extracellular cytotoxic mechanism would be expected to be of significance where the target is too large for ingestion by phagocytosis. The oligosaccharide is anchored to the cell membrane by coupling to a sphingomyelin called ceramide. Eightyfive percent of the population secrete blood group substances in the saliva, where the oligosaccharides are present as soluble polypeptide conjugates formed under the action of a secretor (se) gene. These isohemagglutinins are usually IgM and belong to the class of "natural antibodies" (Table 14. On transfusion, mismatched red cells will be coated by the isohemagglutinins, which will cause severe complementmediated intravascular hemolysis. Maternal antibodies the Rh (rhesus) blood groups form the other major antigenic system. Another disease resulting from transplacental passage of maternal antibodies is neonatal alloimmune thrombocytopenia. The efficacy of Fc fragments and of antiFcR suggests that this works by blockade of the Fc receptors. This test is used for detecting rhesus antibodies and in the diagnosis of autoimmune hemolytic anemia. They react at 37 °C with epitopes on antigens of the rhesus complex distinct from those that incite transfusion reactions. Erythrocytes coated with these antibodies have a shortened halflife, largely through their adherence to splenic macrophages. Similar mechanisms account for the anemia in patients with cold hemagglutinin disease who have monoclonal antiI after infection with Mycoplasma pneumoniae, and in some cases of paroxysmal cold hemoglobinuria associated with the actively lytic Donath­ Landsteiner antibodies specific for blood group P. These antibodies are primarily of IgM isotype and only react at temperatures well below 37 °C. IgG autoantibodies against platelet surface glycoproteins are responsible for the depletion of platelets in idiopathic thrombocytopenic purpura, primarily through Fc receptormediated clearance by tissue macrophages in spleen and liver. Chapter 14: allergy and other hypersensitivities / 421 (a) Examples of this mechanism occur in the hemolytic anemia sometimes associated with continued administration of chlorpromazine or phenacetin, in the agranulocytosis associated with amidopyrine or of quinidine, and in a subset of patients with thrombocytopenic purpura treated with excessive amounts of penicillin. Complexes that are insoluble often cannot be digested after phagocytosis by macrophages and so provide a persistent activating stimulus. The proteolytic enzymes (including neutral proteases and collagenase), kininforming enzymes, polycationic proteins, and reactive oxygen and nitrogen intermediates that are released will, of course, damage local tissues and intensify the inflammatory responses. Further havoc may be mediated by a process referred to as reactive lysis, in which activated C5, C6, and C7 becomes attached to the surface of nearby cells (even though they are not sensitized with antibody) and subsequently binds C8 and C9. Given all these potential consequences of immune complex formation the need for the system of inhibitors present in the body should be absolutely clear. The outcome of the formation of immune complexes in vivo depends not only on the absolute amounts of antigen and antibody but also on their relative proportions, which govern the nature of the complexes and hence their distribution within the body. If the drug forms an immunogenic complex with the surface of circulating blood cells it gains the potential to stimulate the production of antibodies that are cytotoxic for the cell­drug complex. C1q Complement activation Chemotaxis (C5a) Anaphylatoxins (C3a & C5a) Neutrophil Mast cell Release of proteolytic enzymes & polycationic proteins (c) (d) Release of histamine, prostaglandins, leukotrienes, etc. This is an important role of the erythrocyte, a cell often unfairly ignored in discussion of the immune system. If there are defects in this process, for example deficiencies in classical pathway components, or perhaps if the system is overloaded, then widespread disease involving deposition of complexes in the kidneys, joints, skin, and choroid plexus (networks of capillaries in the walls of the ventricles in the brain) may result. Inflammatory lesions due to locally formed complexes the Arthus reaction Maurice Arthus found that injection of soluble antigen intradermally into hyperimmunized rabbits with high levels of precipitating antibody produced an erythematous and edematous reaction that reached a peak at 3­8 hours and then usually resolved. The presence of both antigen and antibody in the intima and media of the arterial wall indicates the deposition of the complexes at this site. Anaphylatoxin (C3a, C4a, and C5a) production, mast cell degranulation, macrophage activation, platelet aggregation, and influx of neutrophils all make their contribution. Inhalation of bacterial spores in dust from the hay introduces antigen into the lungs and an immune complexmediated hypersensitivity reaction occurs. Evidence that an immediate anaphylactic type I response may sometimes be of importance for the initiation of an Arthus reaction comes from the study of patients with allergic bronchopulmonary aspergillosis who have both high levels of IgE and also precipitating IgG antibodies to Aspergillus species. An interesting variant of the Arthus reaction is seen in rheumatoid arthritis, where complexes are formed locally in the joint because of the production of selfassociating IgG antiIgG by synovial plasma cells. Disease resulting from circulating complexes Immune complex glomerulonephritis the deposition of complexes is a dynamic affair and longlasting disease is only seen when the antigen is persistent, as in chronic infections and autoimmune diseases. These acutely inflamed nodules were extremely tender and the patient was pyrexial. Complex deposition is favored in the glomerular capillary because it is a major filtration site and has a high hydrodynamic pressure. Deposition is greatly reduced in animals depleted of platelets or treated with vasoactive amine antagonists. The disease that can follow infection with + certain strains of socalled "nephritogenic" streptococci and the nephrotic syndrome associated with malaria are both well known examples where complexes with antigens of the infecting organism have been implicated. Deposition of immune complexes at other sites the choroid plexuses in the brain are a major filtration site and therefore also susceptible to immune complex deposition. Another example of immune complex hypersensitivity is the dengue hemorrhagic fever and dengue shock syndrome that can occur during a second infection with dengue virus. There are five types of virus, and antibodies to one type produced during a first infection may not neutralize a second strain but rather facilitate its entry into, and replication within, monocytes and macrophages by attachment of the complex to Fc receptors. The enhanced production of virus leads to immune complex formation and a massive intravascular activation of the classical complement pathway. Lane 4: Proteinuria resulting from tubular damage with a totally different electrophoretic pattern. They are often most pronounced on the areas of the face that receive most light exposure. Elimination of microorganisms associated with immune complex disease by chemotherapy may provoke a further reaction because of copious release of antigen. Sodium cromoglycate, heparin, and salicylates are often used, the latter being an effective platelet stabilizer as well as a potent antiinflammatory agent. Corticosteroids are particularly powerful inhibitors of inflammation and are immunosuppressive. In many cases, particularly those involving autoimmunity, conventional immunosuppressive agents such as chlorambucil, cyclophosphamide, or azathioprine may be employed. This kind of hypersensitivity is encountered in many allergic reactions to infectious agents, in the contact dermatitis resulting from sensitization to certain simple chemicals, and in transplant rejection. Histologically, the earliest phase of the reaction is seen as a perivascular cuffing of the blood vessels with mononuclear cells followed by a more extensive exudation of mono and polymorphonuclear cells. This was previously known as "Jones­Mote" sensitivity but is now usually referred to as cutaneous basophil hypersensitivity on account of the high proportion of basophils infiltrating the skin lesion. The stimulated Tcells release a number of cytokines that mediate the ensuing hypersensitivity response, particularly by attracting and activating macrophages if they belong to the Th1 subset, or eosinophils if they are Th2. Cytokines released by Th17 cells cause the activation of various cell types, including macrophages, fibroblasts, and epithelial cells that then release further proinflammatory cytokines which contribute to the pathology. Continual release of cytokines from sensitized Tlymphocytes leads to the accumulation of large numbers of macrophages, many of which give rise to arrays of epithelioid cells (macrophages that differentiate to morphologically resemble epithelial cells), while others fuse to form multinucleated macrophages referred to as giant cells. Further tissue damage will occur as a result of indiscriminate cytotoxicity by cytokineactivated macrophages. It should be noted that granulomas can also arise from the persistence of indigestible antigen­antibody complexes or inorganic materials, such as talc, within macrophages, although nonimmunological granulomas may be distinguished by the absence of lymphocytes. The skin rashes in measles and the lesions associated with herpes simplex infection may be largely attributed to delayed type reactions with extensive Tcmediated damage to virally infected cells. By the same token, specific cytotoxic Tcells can cause extensive destruction of liver cells infected with hepatitis B virus. Cellmediated hypersensitivity has also been demonstrated in the fungal diseases candidiasis, dermatomycosis, coccidioidomycosism and histoplasmosis, and in the parasitic disease leishmaniasis. By contrast, in ulcerative colitis there is a more superficial inflammation involving Th2 cells that is confined to the colon and rectum.

Usage: q.i.d.

The need for the physical union of hapten and carrier is now revealed; the hapten leads the carrier to be processed into the cell, which is programmed to make antihapten antibody and, following stimulus by the Thelperrecognizing processed carrier, it will carry out its program and ultimately produce antibodies that react with the hapten (is there no end to the wiliness of nature By carrying out these transfers with cells from animals bearing a recognizable chromosome marker (T6), it became evident that the antibodyforming cells were derived from the bone marrow inoculum, hence the nomenclature "T" for thymusderived lymphocytes and "B" for antibody forming cell precursors originating in the bone marrow. This convenient nomenclature has stuck even though bone marrow contains embryonic Tcell precursors, as the immunocompetent T and Bcells differentiate in the thymus and bone marrow, respectively (see Chapter 10). The response to tetanus toxoid in neonatally thymectomized animals could be restored by the injection of thymocytes. Different populations of cells from a normal mouse histocompatible with the recipient. They were then primed with a thymusdependent antigen such as sheep red blood cells. The small amount of antibody (Ab) synthesized by animals receiving bone marrow alone is due to the presence of thymocyte precursors in the cell inoculum that differentiate in the intact thymus gland of the recipient. Multiple T cell (red) and Bcell (green) pairs form at the T zone border within a Bcell follicle (arrowheads). Bcells are stimulated by crosslinking surface Ig Bcell activation begins with interaction between antigen and surface immunoglobulin. Once again, it is the accessory molecules associated with the antigen receptor that propagate activation signals into the Bcell. Syk fulfills a critical role within the Bcell activation pro cess; disruption of the gene encoding Syk in the mouse has profound effects on downstream events in Bcell signaling and results in defective Bcell development. Surface IgG was crosslinked with goat antihuman Ig and rabbit antigoat Ig conjugated to 15 nm gold beads (large, dark arrow). Note the clever use of differently sized gold particles to distinguish the antibodies used for localizing the various intravesicular proteins, etc. On the other hand, type 1 Tindependent anti gens, such as the Tcell polyclonal activators, probably bypass the specific receptor and act directly on downstream molecules such as diacylglycerol and protein kinase C, as Ig and Ig are not phosphorylated. Bcells require costimulation via the Bcell coreceptor complex for efficient activation Similar to Tcells, Bcells also require two forms of costimulation to mount efficient effector responses. Imagine a bacterium that has activated complement and has become coated with the products of complement activation, including C3d. To continue the process of maturation to either a plasma cell or a memory cell, the Bcell must now encounter a Tcell capa ble of recognizing one of the antigenic peptides the Bcell is now presenting from the antigen it has internalized. Note that this need not be the same epitope recognized by the Bcell to undergo initial activation. Although Bcells can be stimulated by soluble antigen, it is now widely accepted that the primary form of antigen that triggers Bcell activation in vivo is localized to membrane surfaces. Antigens can be immobilized on cell surfaces by complement or Fc receptors as immunocomplexes, or through direct binding to various scavenger receptors. An encounter between a Bcell and membraneassociated antigen provides the opportunity for the Bcell membrane to spread along the opposing membrane, gathering sufficient antigen to trigger Bcell activation, as well as providing an opportunity for other contacts to be made, such as those that can be provided by membrane integrins. Clearly, spreading along an antigenbearing surface requires extensive reorganization of the cytoskeleton. Although this is not fully understood at present, activation of Vav, which as discussed earlier is involved in the regulation of the cytoskeleton via Rac and Rho, is essential here. Not only do the integrin contacts promote spreading and adhesion between the interacting cell pairs, but recent evidence also suggests that such con tacts lower the threshold for Bcell activation by lowering the concentration of antigen required to form a stable synapse and trigger the Bcell. Top and bottom panels show differential interference contrast and interference reflection microscopy images of the same time points. The raised calcium together with calmodulin also stimu lates calcineurin activity. Differentiation of activated Tcells is controlled by the expression of different master regulators of transcription. Gene expression controlling Tcell activation and differ entiation is under strong epigenetic control. Particular metabolic programs are required for Tcell differentiation into effector subsets. Type 1 thymusindependent antigens are polyclonal acti vators focused onto the specific Bcells by sIg receptors. Type 2 thymusindependent antigens are polymeric mole cules that crosslink many sIg receptors and, because of their long halflives, provide a persistent signal to the Bcell. Thymusdependent antigens require the cooperation of helper Tcells to stimulate antibody production by Bcells. The ability of protein carriers to enable the antibody response to haptens is explained by Tcell­Bcell collaboration, with Tcells recognizing the carrier and Bcells the hapten. The adaptive immune response works in tandem with an ongoing innate immune response and, as we shall see, amplifies and reinforces the innate immune response through the provision of cytokines, antibodies, and cytotoxic Tcells capable of executing virally infected cells. Activated Tcells differentiate into effector cells capable of secreting diverse patterns of cytokines or cytotoxic molecules; similarly, activated Bcells differentiate into plasma cells capable of secreting different antibody classes. This is achieved through the secretion of different patterns of cytokines in response to the initial infection. These cytokines, in turn, influence the nature of the T and Bcell effectors that are produced. Cytokines can also stimulate production of additional innate immune cells, such as macrophages and neutrophils, can increase the production of acute phase proteins, and promote dilation of local blood vessels to facilitate migration of immune cells to the site of infection. As the reader will hopefully recall from earlier chapters, cytokines are soluble cell­cell communication molecules that enable cells of the immune system to "talk" to other immune cells, instructing the recipients of these signals to switch on particular functions. Cytokines that are important for the initiation and/or amplification of immune responses can also be released from barrier tissues, such as skin keratinocytes or intestinal epithelium, thus enabling these nonimmune cells to play a role in the initiation and shaping of immune responses. We shall now look at the various classes of cytokines that are important within the immune system, how their production is regulated, how they convey their messages intracellularly, and how the various cytokines and cytokine combinations influence the various effector functions of the T and Blymphocytes of the adaptive immune system. As we also learned in Chapter 1, the nature of the infectious agent (whether viral, bacterial, or yeast, etc. This sets the ball rolling in terms of tailoring the innate as well as the subsequent adaptive immune response towards what is most useful for a particular infectious agent. As we shall see throughout this chapter, particular cytokine combinations trigger the differentiation of T and Bcell populations into distinct effector classes. Effector mechanisms of innate and adaptive immunity the innate immune system utilizes a number of different effector mechanisms to combat infection In Chapter 1 we learned that the innate immune system uses a variety of strategies to deal with microorganisms that have successfully breached the physical barriers of the skin and mucosal surfaces. Macrophages and neutrophils also directly recognize and engulf pathogens via their cellassociated pattern recognition receptors. As we also learned in Chapter 1, neutrophils can release their cytotoxic enzymes into the extracellular space through degranulation, and can even deploy their chromatin as extracellular traps for microorganisms, attacking and killing infectious agents through destructive proteases and carbohydrases. Other options at the disposal of the innate immune system involve the deployment of mast cells and basophils, both of which use their granule enzymes to combat large extracellular parasites. All told, the innate immune system has a truly impressive armory of highly effective weapons that can be deployed in pursuit of defending the body against infection. Nonetheless, the innate immune system frequently requires assistance to deal with welladapted pathogens that have evolved an equally impressive array of immune evasion strategies to frustrate all of the above efforts. For the most part, the effector mechanisms of the innate immune system also lack memory of previous encounters with regular visitors (although recent discoveries suggest that innate immunity does have some capacity for memory) and have to start from scratch each time a new infection occurs. Moreover, stockpiles of particularly useful T and Bcells can also be generated through clonal expansion and maintained for many years as memory cells. The latter cells can be deployed rapidly when regular guests come calling, giving a considerable advantage over an unsuspecting pathogen. However, there is a very troublesome fly in the immune ointment that cannot be overlooked. This is a critical role of the innate immune system and its importance cannot be overstated. Thus, cells of the innate immune system, in effect, give permission to cells of the adaptive immune system to respond to antigen. In Chapter 2 we discussed the role of Bcellderived antibodies as a means of coating microorganisms for the purposes of enhancing complement mediated lysis via the classical pathway, or enhancing their uptake by phagocytosis via specific Fc receptors on macrophages and neutrophils, or indeed by simply aggregating infectious agents and impeding their further incursion into tissues. As we shall discuss in more detail in this chapter, Thelper cells can be further subdivided into Th1, Th2, Th17, and Tfh cells on the basis of the cytokine profiles that these cells secrete, as this confers different effector functions on such cells. We shall also discuss other subdivisions of Tcells (regulatory Tcells [Tregs]), that also differ in the cytokine profile produced, as these cells serve important regulatory functions and help to safeguard the body against inappropriate Tcell responses that are directed against self, as well as excessive or inappropriate responses directed towards nonself. This illustrates some, but by no means all, of the interactions that activated Tcells can have with other elements of the immune system through the directed secretion of specific cytokines. Rather, specific Tcell subsets are generated that are skewed towards secretion of particular subsets of the cytokines shown. Chapter 8: the production of effectors / 223 Production of cytokines by Tcells to promote antibody production by Bcells Production of cytokines by Tcells to promote wound healing. Cytokines influence the generation and function of effectors within the adaptive immune system As noted above, the production of various cytokines in response to the detection of pathogens by the innate immune system is central to both the maturation as well as the specific effector functions of B and Tcells. We have already referred to the diverse roles of cytokines throughout the previous chapters and have alluded to their properties as messenger molecules that enable the disparate elements of the immune system to communicate with each other and also to trigger differentiation to particular effector cell types. Here, we will go into more detail concerning the different categories of cytokines, how these molecules act upon their target cells, and the spectrum of responses they initiate. All of these issues are central to how the effector cells of the adaptive immune system are generated and the nature of the responses they engage in. Dendritic cells and other cells of the innate immune system play a central role in the generation of effectors A major influence on the type of effector cells generated in response to a pathogenic challenge is wielded by dendritic cells, which, in addition to presenting antigen (signal 1) and providing costimulatory signals (signal 2) to Tcells, also exert significant control over the type of Tcell response that is generated. Once again, this is through the provision of cytokines that trigger or reinforce the development of different Tcell effector subsets. Note that the cytokine environment upon restimulation of a Tcell within an infected tissue will also influence the nature of the effector response made by the Tcell. This information is translated, via the actions of the multiplicity of pattern recognition receptors, into a unique cytokine signature that is instrumental in shaping the type of immune response that is initiated to deal with the particular infection. Macrophages can undergo polarization into different subpopulations that make different cytokine combinations There is much evidence that macrophages, which are highly abundant in most tissues as we discussed in Chapter 1, can also undergo polarization to express distinct cytokine combinations. At a minimum, two major macrophage populations have been identified, designated M1 (or classically activated) and M2 (or alternatively activated) macrophages. The presence of polarized macrophages populations within tissues can skew adaptive immune responses towards eliciting Tcell populations that favor cytotoxic Tcell responses, or those that give help for Bcellmediated production of IgE, or through suppressing the development of such responses. However, it really cannot be overemphasized that the separation of macrophages into sharply defined M1/M2 subsets is a gross oversimplification. The real situation is much more akin to a color palette, with each shade of the color spectrum representing distinct macrophage types expressing distinct subsets of cytokines, chemokines, antimicrobial peptides, and other effector molecules. Macrophage populations are highly diverse and there is a growing body of evidence to suggest that this diversity is underpinned by the unique tissue environment experience by individual macrophages. As a consequence, there are large differences between the phenotypes and functional properties of macrophages from different tissues, such as Kupffer cells in the liver, alveolar macrophages of the lung, peritoneal macrophages, microglial cells in the brain, and so on. The nature of the factors that trigger macrophage polarization are only now being identified, but retinoic acid, tissue osmolarity, prostaglandins, and lactic acid are some of the factors that have been shown to activate distinct transcription factor programs that promote macrophage polarization. Before we discuss the various T and Blymphocyte effector cell types, let us now take a closer look at the diversity of the cytokine family and how these important cell­cell communication molecules exert their effects at a molecular level. Cytokines signal via plasma membraneborne receptors, to which they bind with very high affinity, and generally show very high specificity towards their receptors. As a result of the very high affinity for their cognate receptors, cytokines are frequently biologically active at very low concentrations, typically in the nanomolar (10-9) or even picomolar (10-12) range. Cytokines can promote cell division, can trigger the production of additional cytokines, chemokines, and antimicrobial peptides; others can promote cell death or cell differentiation. Cytokines also exhibit pleiotropic effects, eliciting one response in a specific cell type and a completely different response in another. Chapter 8: the production of effectors / 225 between cells, to switch on, or off, specific effector functions or to initiate the process of differentiation from one cell state to another. To date, many different cytokines have been described and no doubt some remain to be discovered (Table 8. Other cytokine families have been established on the basis of their ability to support proliferation of hematopoietic precursors (colonystimulating factors), or cytotoxic activity towards transformed cell types (tumor necrosis factors), or the ability to interfere with viral replication (interferons). It is important to note, however, that cytokines frequently have pleiotropic effects, doing much more than their somewhat descriptive (and often misleading) names would suggest. Indeed, the response that many of these molecules elicit depends, to a large extent, on the context in which the cytokine signal is delivered. Other factors, such as the differentiation stage of the cell, its position within the cell cycle (whether quiescent or proliferating), and the simultaneous presence of other cytokines, can all influence the response made to a particular cytokine. Cytokine action is transient and usually short range Cytokines are typically low molecular weight (15­25 kDa) secreted proteins that mediate cell division, inflammation, cytotoxicity, differentiation, migration, and repair. Role in activationinduced Tcell apoptosis Induction of Th2 cytokines; mediates chemotaxis of basophils and mast cells Stimulates Mono proliferation and formation of macrophage progenitors Immunosuppressive effects on Th1, Th2, and Th17 cells. Stimulates proliferation of Tregs Activates Mono, macrophages, keratinocytes to produce multiple proinflammatory cytokines. This designation was given to an activity that, upon further investigation, could not be unambiguously assigned to a single cytokine. Illustrated here are three of the main types of structure and some named examples of each type: (a) four short (15 amino acids) helices, (b) four long (25 amino acids) helices, and (c) a sheet structure. Thus cytokines derived from lymphocytes rarely persist in the circulation, but nonlymphoid cells, such as endothelial cells and fibroblasts, can be triggered by bacterial products to release cytokines that may be detected in the bloodstream, often to the detriment of the host. As we shall see later, cytokine production and downstream effector function are kept under tight control at multiple levels, transcriptional, translational, as well as through use of decoy receptors (which bind cytokines but do not signal) and cytokine receptor antagonists (which compete with cytokines for binding to their cognate receptors). Chapter 8: the production of effectors / 229 Alternative functions of cytokines Although cell­cell communication is the primary function of cytokines, emerging reports suggest that certain cytokines may also have direct effector functions as antimicrobial proteins. Although this aspect of cytokine function may be rare, it is worth bearing in mind that certain cytokines may have dual roles, just as complement factors (such as C5) can have direct antibacterial effects as well as serving as chemotactic factors for neutrophils and activators of mast cells. Thus, although all cytokines and chemokines are important in their own way, some cytokines act as apical or upstream regulators of many additional inflammatory factors, while others act in a more distal or downstream role.